Like many of you, I follow a number of pharmaceutical industry discussion groups on LinkedIn. Some of these groups have taken on lives of their own, becoming like group blogs.
Still, discussions often revolve around one central theme: regulatory reaction and acceptance.
As I’ve written in the past, those working in the pharmaceutical industry today are far more comfortable being told what to do by regulators than figuring out how to reach regulatory goals by themselves.
Is this one of the reasons why pharma has not yet wholeheartedly embraced FDA’s process analytical technology (PAT) guidance?
One topic of PAT-related debate that is now floating around the LinkedIn groups, and to which an entire session was devoted at the last American Association of Pharmaceutical Scientists’ (AAPS) annual meeting, is real-time release (RTR).
What is RTR, and how does it differ from RTR testing (RTRT)?
Some diehard PAT devotees are not willing to give up RTR, and view it as being distinct from RTRT as defined in ICH Q8 (R2).
According to the FDA guidance on ICH documents, RTRT does not impact batch release, nor does it eliminate end-product testing. The FDA guidance even addresses OOS investigation within RTRT. Consequently, RTRT is a “tool,” and a replacement for slower analytical techniques. For example, dissolution is replaced with a calibrated NIR instrument.
RTR, on the other hand, was defined in the PAT Guidance to facilitate product release based on the “combined process measurements and other test data gathered during the manufacturing process” which “can serve as the basis for real-time release of the final product,” demonstrating “that each batch conforms to established regulatory quality attributes.”
EMA defines RTRT as the set of in-process controls that, under specific conditions, “may provide greater assurance of product quality than end-product testing.” RTRT, along with product knowledge and enhanced process understanding and control, the regulators write, enables RTR, a system of product release that provides assurance that the product is of intended quality.
On the face of it, EMA’s definition is closer to that of the PAT guidance, and in practice RTRT and RTR seems to be worlds apart.
But, instead of focusing on the differences between the two terms, shouldn’t we consider each in light of supply chain logistics and financial needs?
Control your process in real time, and do what is right to give you an efficient and agile manufacturing process, good quality product, and a quality assurance on par with other manufacturing industries. In other words: Just do what makes economic and scientific sense.
For example, a friend and colleague recently explained that, at his facility, two hours per batch are saved by using RTRT, which—it was assumed—would result in huge savings per year. On further inquiry, however, it became evident and obvious that the impact on batch release was zero, as RTRT had improved and enhanced the analytical testing, but moved the bottleneck downstream and neither the product quality nor the manufacturing cycle were affected.
Aristotle’s words, from “The Nicomachean Ethics,” come to mind: “It is clear that there is a difference in the ends; for the ends are sometimes activities, and sometimes results beyond the mere activities.”
As other industries have shown us, an agile supply chain can only exist in a just-in-time environment. In pharma, JIT is RTR.
Any time we try to define a term in abstraction, divorced from action, we create a solution in search of a problem.
We don’t need to search for problems in pharma. They’re all around us.
Whether we call the solution RTR or RTRT, we need to ask some questions: does it reduce the stockpile, increase process efficiency or shorten overall cycle time? If not, who cares what it is called or whether it is even used? It’s just an added expense, a waste of time and energy, and technology for its own sake
A vision should create the desire for action, but only action will yield clarity of vision.
And a realistic action plan is exactly what is lacking in these RTR vs. RTRT debates.
Without it, thoughts remain abstract, and the regulatory environment controls all. In this environment, innovation becomes impractical. Maintaining the status quo becomes the norm, and ignorance of best practices a safe haven and comfort zone.
Are you shocked? Let me ask you a few rhetorical questions:
• What is the process sigma of each of your batches?
• Are you comfortable increasing your sample size for batch release?
• How comfortable are you with scaleup?
• Do you understand the impact of raw material variability to a point where you could willingly, and regularly, change your suppliers in response to changing economic conditions?
Right now, most pharma professionals decide whether or not to use RTR or RTRT based, not on business or supply chain needs, but on what they think the FDA would say.
Is it acceptable for manufacturers to allow regulators to dictate how their facilities are run? Not a single regulator, reviewer or inspector, anywhere in the world would agree to do this. Yet that is the outcome, by default.
The PAT Guidance tried to address, in a non-prescriptive manner, the supply chain issues with RTR.
The problem today, and it is a desperate one, is not “What will the regulator say?" or "How do I appease the regulator?" Instead it is: “How do we bring innovation to drug manufacturing, and quality assurance to the pharmaceutical industry?”
What should our industry’s action plan be? I would love to hear your thoughts. Please email me at email@example.com, via LinkedIn, or pharmaqbd.com.